Compounds with modifying activity enhanced under hypoxic conditions

Patent metadata

Field	Value
Publication number	US-9816075-B2
Application number	US-201414531774-A
Country	US
Kind code	B2
Filing date	Nov 3, 2014
Priority date	Aug 2, 2005
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

Compositions and methods for modifying one or more biologic targets are provided. Suitable targets include cells, DNA, proteins, enzymes, and/or a subject in need thereof. The compositions may exist as a monomer or multimer and are active in a biologic environment with enhanced activity in hypoxic environments and, thus, exhibit improved specificity for hypoxic biologic targets (e.g., tumorigenic cells and those undergoing uncontrolled cell growth). A composition typically comprises a complex with an overall charge of 2+ or greater having at least one ruthenium atom attached to a redox active ligand. The redox active ligand helps maintain separation of more than one ruthenium atom. Suitable compositions may further include a terminal ligand comprising a heterocyclic aromatic compound. When provided to a biologic target, the composition modifies the biologic target and no additional compounds need be provided. Suitable compositions are typically catalytic and regenerative in the presence of a reducing agent.

First claim

What is claimed is:

1. A method of modifying a cell undergoing uncontrolled cell growth comprising the steps of:
providing a complex to the cell, wherein the complex comprises at least one ruthenium atom complexed to a first ligand that is a heterocyclic aromatic compound and to a second ligand that is redox active, wherein the second ligand comprises tatpp or tatpq and has a reduction potential that is accessible in a cellular milieu;
reducing the redox active ligand of the complex with a reducing agent present in the cell to form a reduced complex; and
modifying the cell with the reduced complex, wherein said modification of the cell comprises breaking one strand of DNA, breaking two strands of DNA in close proximity, inhibiting topoisomerase I, inhibiting topoisomerase II, inhibiting impulse transmission, inhibiting cell proliferation, inhibiting cell growth, inhibiting DNA replication, inhibiting DNA duplication, inhibiting tumor progression, inhibiting tumor growth, or combinations thereof, wherein said complex is active on cisplatin resistant cells that are undergoing uncontrolled cell growth, cells on which cisplatin is inactive that are undergoing uncontrolled cell growth, or both.

2. The method of claim 1 , wherein the first ligand comprises pyridine, pyrimidine, ethylenediamine, 1,10-phenanthroline, 2,2′-bipyridine, or 1,10-phenanthroline-5,6-dione.

3. The method of claim 1 , wherein the complex has the formula [Ru(X) 2 tatpp] 2+ or [Ru(X) 2 tatpq] 2+ , and their salts and stereoisomers thereof, and X is a heterocyclic aromatic compound.

4. The method of claim 3 , wherein X comprises pyridine, pyrimidine, ethylenediamine, 1,10-phenanthroline, 2,2′-bipyridine, or 1,10-phenanthroline-5,6-dione.

5. The method of claim 1 , wherein the complex further includes a pharmaceutical carrier.

6. The method of claim 1 , wherein reduction of the redox active ligand is more favorable in a hypoxic environment and the modification of the cell is enhanced.

7. The method of claim 1 , wherein the reduced redox active ligand is regenerated by a cellular oxidant and is catalytic in its modification of the cell.

8. The method of claim 1 , wherein the complex has the formula [Ru(phen) 2 tatpp] 2+ or [Ru(phen) 2 tatpq] 2+ .

9. The method of claim 1 , wherein the complex has the formula [Ru(phen) 2 tatpp] 2+ .

10. The method of claim 1 , wherein the modification of the cell comprises breaking one strand of DNA, breaking two strands of DNA in close proximity, or a combination thereof.

11. The method of claim 1 , wherein the method is performed under hypoxic conditions.

12. The method of claim 1 , wherein besides the reduced complex, no additional reagent is used for the modification.

13. A method of modifying a cell undergoing uncontrolled cell growth comprising the steps of:
providing a complex to the cell, the complex having a formula selected from [Ru(X) 2 tatpp] 2+ , [Ru(X) 2 tatpq] 2+ , and salts and stereoisomers thereof, wherein tatpp and tatpq are redox active ligands and X is a heterocyclic aromatic compound, wherein tatpp or tatpq are redox active ligands that has a reduction potential that is accessible in a cellular milieu;
reducing the redox active ligand of the complex with a reducing agent present in the cell to form a reduced complex; and
modifying the cell with the reduced complex, wherein said modification of the cell comprises breaking one strand of DNA, breaking two strands of DNA in close proximity, inhibiting topoisomerase I, inhibiting topoisomerase II, inhibiting impulse transmission, inhibiting cell proliferation, inhibiting cell growth, inhibiting DNA replication, inhibiting DNA duplication, inhibiting tumor progression, inhibiting tumor growth, or combinations thereof, wherein said complex is active on cisplatin resistant cells that are undergoing uncontrolled cell growth, cells on which cisplatin is inactive that are undergoing uncontrolled cell growth, or both.

14. The method of claim 13 , wherein X comprises pyridine, pyrimidine, ethylenediamine, 1,10-phenanthroline, 2,2′-bipyridine, or 1,10-phenanthroline-5,6-dione.

15. The method of claim 13 , wherein the complex further includes a pharmaceutical carrier.

16. The method of claim 13 , wherein the complex has the formula [Ru(phen) 2 tatpp] 2+ .

17. The method of claim 13 , wherein the modification of the cell comprises breaking one strand of DNA, breaking two strands of DNA in close proximity, or a combination thereof.

18. The method of claim 13 , wherein the method is performed under hypoxic conditions.

19. The method of claim 13 , wherein besides the reduced complex, no additional reagent is used for the modification.

20. A method of modifying a cell undergoing uncontrolled cell growth comprising the steps of:
providing a complex to the cell, the complex having a formula selected from [Ru(phen) 2 tatpp] 2+ , [Ru(phen) 2 tatpq] 2+ , and salts and stereoisomers thereof, wherein tatpp and tatpq are redox active ligands, that has a reduction potential that is accessible in a cellular milieu;
reducing the redox active ligand of the complex with a reducing agent present in the cell to form a reduced complex; and
modifying the cell with the reduced complex, wherein said modification of the cell comprises breaking one strand of DNA, breaking two strands of DNA in close proximity, or a combination thereof, wherein the method is performed under hypoxic conditions, and wherein besides the reduced complex, no additional reagent is used for the modification.

Assignees

• Univ Texas

Inventors

• Macdonnell Frederick M
• Janaratne Thamara K
• Awashti Sanjay

Classifications

• C12N5/0693 Primary

  Tumour cells; Cancer cells · CPC title

• C07F15/0053 Primary

  without a metal-carbon linkage · CPC title

• C07F15/0046

  Ruthenium compounds · CPC title

• A61K31/435

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• C12N2500/10

  Metals; Metal chelators · CPC title